In the medical and veterinary fields, there is need and long felt want to provide improved long acting compositions. A significant advantage of utilising long acting compositions is the ability to administer the composition on a less frequent basis. This equates to less stress, time and hardship to the patient or animal, as well as the caregiver. Less consumables and storage of the composition is also required, also giving significant advantages.
Whilst there are many known bio-active agents already in use, it can often be difficult to provide these in compositions with good pharmacokinetic properties, including in this case, long acting delivery profiles.
Problems often persist with poor stability or solubility of the actives, uncontrolled or unwanted release profiles, poor knockdown affects or unwanted side effects following administration.
For example, in the field of veterinary medicine, anthelmintics are used to control or treat internal and external parasites. There is a wide variety of different anthelmintics and derivatives to utilise when treating such parasites. However, many anthelmintics, such as macrocyclic lactones, are poorly soluble in conventional solvents. They are particularly difficult to administer in an injectable format, which is typically used for long acting protection against ecto- and endoparasites.
Macrocyclic lactone compounds such as avermectins, ivermectin, doramectin, mibemycin and moxidectin can easily break down in water-based compositions.
To try to counter this issue, formulation chemists have included such actives together with excipients such as glycol solvents, glycerol formal and/or surfactants.
However, an additional significant problem encountered with many anthelmintic compositions, many of which attempt to provide a long acting persistence, is that the macrocyclic lactone is released too rapidly in the animal. This leads to a shorter duration of protection from the active, disadvantageously requiring re-administration on a more regular basis.
It can also be very dangerous to animals to be exposed to high levels of the bioactive agent (e.g. a macrocyclic lactone), especially younger animals such as calves under the age of 10 weeks. A further problem is therefore trying to avoid an uncontrolled release profile of the active to avoid toxic results.
Furthermore, it is often be beneficial to provide a controlled “burst” of an active agent to provide an initial “knockdown effect” to help rid the body of parasites. This controlled burst can then be followed with a long acting slow release of the anthelmintic to help ensure the parasites are completely removed, or provide long term protection.
A controlled profile release such as this can be difficult to achieve, especially in a single long acting composition. This is especially true for precarious actives such as anthelmintics. Even if such a release is achieved, it often comes at the expense of complicated combination of excipients, increased labour in manufacture, equipment or other resources in preparing the composition.
Injectable compositions can be especially troublesome to formulate as long acting compositions. For instance, many of the excipients used such as polymers, glycols, alcohol based solvents and so forth can lead to unwanted characteristics such as high viscosity in the composition which can make it difficult to administer through a needle. Similarly, some of the excipients used in long acting injectables can lead to an increased site reaction on injection. Also, some compositions can have poor storage characteristics. Furthermore, despite attempting to provide a long acting release of active and therefore persistency of protection, many fall short of this goal.
WO 97/11709 (Harvey) discloses an anthelmintic lactone composition including a vegetable oil and a co-solvent chosen from an alcohol having four or more carbon atoms, such as benzyl alcohol.
U.S. Pat. No. 6,552,002 (Steber) discloses sustained-release compositions including a macrocyclic lactone compound at a high concentration (between 5-30% w/w), together with a surfactant (described as sorbitan esters), a solvent and co-solvent.
Steber discusses that by increasing the active concentration above what is normally used, a sustained release of the active is possible. However, higher loading of actives can be dangerous due to toxicity problems as previously discussed.
Furthermore, the higher concentration of active needed to provide the sustained release profile in Steber requires a complicated combination of excipients. Despite these requirements, it is likely the high loading of active could inherently lead to stress on the composition, leading to a diminished shelf life. Other downfalls include likely higher costs in preparation and/or a greater site reaction on delivery.
U.S. Pat. No. 6,174,540 (Williams) discloses long acting injectable formulations including a therapeutic agent (e.g. insecticides, parasiticides, NSAIDs, etc) together with hydrogenated castor oil, a hydrophobic carrier (triacetin, benzyl benzoate, or ethyl oleate), and one of acylated monoglycerides, propyl dicaprylates/dicaprate, or caprylic/capric acid triglycerides). Williams found that the combination of excipients identified, as expected, had the ability to provide a long acting release profile to a range of bioactives.
NZ 332224 (Grosse-Bley) also discloses injectable formulations including avermectins and mibemycins which include castor oil together with an additional co-solvent selected from fatty acid esters of mono- or polyhydric alcohols, aliphatic or aromatic alcohols, or cyclic carbonates.
WO 2007/024719 (Soil) discloses long acting injectable formulations for treating ectoparasites and endoparasites, wherein the formulation includes the bioactive agent, a subcutaneously volatile solvent, a biologically acceptable polymer, together with additional optional excipients. The use of polymers especially was discussed as allowing the release profile to extend up to 42 days.
EP 393890 (Wicks) discloses the use of a combination of ethyl oleate (a fatty acid ester) and sesame oil as a solvent for avermectin compounds. These formulations were found to be well tolerated when administered as an injection. However they lack storage stability, with a precipitate forming after a few days when stored at 4° C.
WO 2010116267 (Costa) discloses high-dose injectable formulations of doramectin at 3.5% in a carrier of cottonseed oil and benzyl benzoate. A comparative example is a formulation from NZ 332224 (Grosse-Bley), containing 3% doramectin in a carrier of 40% v/v castor oil and 60% v/v ethyl oleate. Costa provides a comparison of the efficacy in treating screwworm (the larvae of the myiasis-causing fly Cochliomyia hominivorax), between the disclosed cottonseed oil/benzyl benzoate composition and the comparative castor oil composition in Grosse-Bley. The results showed that the release of active from the castor oil formulation is either delayed or relatively slow, so that an efficacious systemic concentration is reached noticeably later than the cottonseed/benzyl benzoate formulation. It was suggested that the high affinity of castor oil for avermectins such as doramectin, unfavourably slows the release of the drug from the carrier.
A currently available commercial product Cydectin® Long Acting Injection for Sheep is marketed as a long-acting formulation containing moxidectin. This product is indicated to prevent reinfection with Haemonchus contortus for 91 days, Ostergia circumcincta for 112 days and Trichostrongylus colubriformis for 42 days following a single dose. Preliminary studies performed by the current inventors assessed larvae counts from hatched eggs from faecal samples. This study found that Cydectin® Long Acting provided a reduced egg count for up to about 100 days.
Furthermore, Cydectin can lead to site reaction (e.g. swelling and inflammation) at the injection site in animals following administration.
There is a long felt need to provide stable, long acting formulations that can provide protection against parasites for longer duration than currently available compositions like Cydectin®.
Even more so, there is a need to provide a formulation that provides a treatment that allows a fast yet controlled “bleed” to provide a good initial knockdown effect to quickly control the condition in the animal, yet then still provide a longer acting protection to the animal.
Despite the attempts in the industry to formulate long acting compositions, the problems outlined above continue to persist.
It is an object of the present invention to address the foregoing problems or at least to provide the public with a useful choice.
All references, including any patents or patent applications cited in this specification are hereby incorporated by reference. No admission is made that any reference constitutes prior art. The discussion of the references states what their authors assert, and the applicants reserve the right to challenge the accuracy and pertinency of the cited documents. It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents form part of the common general knowledge in the art, in New Zealand or in any other country.
Throughout this specification, the word “comprise”, or variations thereof such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
Further aspects and advantages of the present invention will become apparent from the ensuing description which is given by way of example only.